Ligand and Structure-Based In Silico Determination of the Most Promising SARS-CoV-2 nsp16-nsp10 2'- o -Methyltransferase Complex Inhibitors among 3009 FDA Approved Drugs.

As a continuation of our earlier work against SARS-CoV-2, seven FDA-approved drugs were designated as the best SARS-CoV-2 nsp16-nsp10 2'- o -methyltransferase (2'OMTase) inhibitors through 3009 compounds. The in silico inhibitory potential of the examined compounds against SARS-CoV-2 nsp16-nsp10 2'- o -methyltransferase (PDB ID: (6W4H) was conducted through a multi-step screening approach. At the beginning, molecular fingerprints experiment with SAM ( S -Adenosylmethionine), the co-crystallized ligand of the targeted enzyme, unveiled the resemblance of 147 drugs. Then, a structural similarity experiment recommended 26 compounds. Therefore, the 26 compounds were docked against 2'OMTase to reveal the potential inhibitory effect of seven promising compounds (Protirelin, ( 1187 ), Calcium folinate ( 1913 ), Raltegravir ( 1995 ), Regadenoson ( 2176 ), Ertapenem ( 2396 ), Methylergometrine ( 2532 ), and Thiamine pyrophosphate hydrochloride ( 2612 )). Out of the docked ligands, Ertapenem ( 2396 ) showed an ideal binding mode like that of the co-crystallized ligand ( SAM ). It occupied all sub-pockets of the active site and bound the crucial amino acids. Accordingly, some MD simulation experiments (RMSD, RMSF, R g , SASA, and H-bonding) have been conducted for the 2'OMTase-Ertapenem complex over 100 ns. The performed MD experiments verified the correct binding mode of Ertapenem against 2'OMTase exhibiting low energy and optimal dynamics. Finally, MM-PBSA studies indicated that Ertapenem bonded advantageously to the targeted protein with a free energy value of -43 KJ/mol. Furthermore, the binding free energy analysis revealed the essential amino acids of 2'OMTase that served positively to the binding. The achieved results bring hope to find a treatment for COVID-19 via in vitro and in vivo studies for the pointed compounds.